Four new tris-substituted bismuth(III) sulfonates of general formula [Bi(O3SR)3] (R = phenyl 1, p-tolyl 2, 2,4,6-mesityl 3 and S-(+)-10-camphoryl 4) have been synthesised and characterised. Their synthesis by solvent-free (SF) and solvent-mediated (SM) methods has been explored and their activity against Helicobacter pylori has been investigated. The compounds 1–4 display a remarkable in vitro activity against three laboratory strains of H. pylori (B128, 26 695 and 251) with minimum inhibitory concentration (MIC) values as low as 0.049 μg mL−1 for the strains B128 and 26 695, and 0.781 μg mL⁻¹ for the clinical isolate 251. This places most MIC values in the nano-molar region and demonstrates the strong influence of the sulfonate group on the bactericidal properties. The novel solid state structure [Bi₈(O₃SMes)₂₀(SO₄)₂(H₂O)₆]·(C₇H₈)₇₅·(C₇H₈)₇, derived from the SM reaction under reflux conditions, is presented and the incorporation of the two inorganic sulfate anions in the centre of the wheel-like bismuth sulfonate cluster explained.